The interaction of viruses with dendritic cells is believed to play a key role in determining whether protective Th1 responses or less effective Th2 responses are generated. Our data are consistent with the hypothesis that for DC to generate Th1 immunity they must achieved maximum maturation. Such maturation can be achieved by incubating DC with bacteria, LPS, CpG, inflammatory cytokines or by virus infection. We have evidence that whereas live virus induces Th1 cells, inactivated viral leads to expansion of Th2 cells. Accordingly, evidence strongly suggests a role for elements of the interferon pathway in generating Th1 immunity. For example, interferon regulatory factors have been shown to play a role in IL-12 production and responsiveness to gamma interferon and mice deficient in interferon regulatory factors are unable to generate effective Th1 responses. We speculate that in contrast to live virus, inactivated virus is unable to prime for Th1 immunity results from its failure to activate the interferon pathway leading to DC maturation. In particular, we propose to examine interferon virus NS1 mutants because evidence exists that they are even more effective than wild type virus in activating the interferon pathway and hence may be more potent inducers of DC maturation and Th1 immunity. We also propose to employ DC from mice genetically deficient in different elements of the interferon pathway to more precisely define the molecular events associated with DC maturation. Finally, we propose to apply information gained from earlier experiments to create a protocol whereby the Th2 response normally seen with inactivated virus can be converted to a Th1 response. It should be emphasized that the importance of the results obtained may not primarily bear on influenza virus vaccines but may have important implications for non-replicating vaccines where a Th1 immune response is deemed valuable.